zE ABSTRACT This is a renewal RO01l aplliicatiionto study receptor editing, which is a mechanismof immune tolerance involving secondary immunoglobulin (lIg) light chain rearrangements that change B cell receptor (BCR) specificity. Collectively, receptor editing mechanisms promote tolerance by reprogrammiingBcelspecifiiciity,,rattherrthanthroughclolonall deletion. The long term goal of these studies is to understandthe mechanismsthat controltthesiginalilninganadndexeexceuctuiotionnooffrerecceptotorrediitiing. '-" 0)a) = Ox) Non autoreactive BCRs expressedby developingBcelspromottedevelolopmentatall progressionand the cessation of V(D)J recombination(positive selection),whereas autoreactive receptors promote ongoing L-chain gene recombinationandediting.These divergent biological outcomes relyon the qualityofthesiignallsgenerattedbyan innocuous vs autoreactive BCRs. In this applicationwe proposetostudyGSK3a, a protein kinase regulatedby BCR signalingthatappearstopllayarolleiinprromotitning receptor editing. These studies will involveanalysisofcellllliine,,mouseknockoutsts,,andB cell overexpression modelsto obtain acomprehensiiveviewoftherolelesoffGSK3cai in receptorediting.. -CD ='a -TM a)N (n0 -,cam The SpecificAim of this proposalis as folows: . 3 3 v Aim 1. To determineiifandhowGSK3aregulalatetesrreceptotorreditiitning.. The studieswil alsoaddrestherellattedquesttiionoffhowandwhytthecloloselylyrrelalateted protein GSK3P is poorly activated by BCR signaling in immature B cells. ARRA Response:2 R01 A1033608-16A1 ARRA Response: 2 ROl A1033608-16A1 F-- protein GSK3$3 is poorly activated by BCR signaling in immature B cells. L-'